Performance of Xpert MTB/RIF ultra for the diagnosis of tuberculous meningitis in children using cerebrospinal fluid

Rapid and reliable diagnostic tests for tuberculous meningitis (TBM) in children remain limited. This study evaluated the performance of Xpert MTB/RIF Ultra (Ultra), an improved version of Xpert MTB/RIF (Xpert), for detecting TBM in children using cerebrospinal fluid (CSF). Children (0-14 years) presumptive of TBM were enrolled prospectively from three tertiary level hospitals in Dhaka, Bangladesh, from December 2019 to January 2022. CSF was tested by Ultra, Xpert, Lowenstein-Jensen (L-J) culture, and acid-fast bacilli (AFB) microscopy. Diagnostic performance was assessed against clinical case definitions, composite microbiological reference standard (CMRS), and L-J culture. Of 187 children, Ultra detected TBM in 23.4% of cases, significantly higher than the 9.1% detected by Xpert (p < 0.001). Compared to the clinical case definition of probable and definite TBM, Ultra exhibited a sensitivity of 88% (44/50), markedly outperforming Xpert (34%, 17/50) and L-J culture (30%, 15/50) (p < 0.001). Against the CMRS, Ultra's sensitivity was 100% (44/44), compared to Xpert (38.6%, 17/44) and L-J culture (34.1%, 15/44) (p < 0.001). AFB microscopy showed very low sensitivity (2.3%, 1/44). Negative predictive values for both clinical case definition and CMRS were higher for Ultra (95.8-100%) than Xpert (80.6-84.1%) and L-J culture (79.7-83.1%) (p < 0.001). Compared to gold standard L-J culture, Ultra's sensitivity (100%, 15/15) was also higher than Xpert (93.3%, 14/15) (p = 0.316), with specificities of 83.1% (143/172) and 98.3% (169/172), respectively. Ultra detected 26 TBM cases missed by other tests, with most (84.6%) in the 'trace detected' category. Due to the high performance, Ultra can be used widely at health care settings of high TB burden countries like Bangladesh for rapid and accurate diagnosis of paediatric TBM using CSF samples.